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Cited by 80Cancer, Hypoxia, and MetabolismHistone Deacetylase Inhibitors ResearchCancer, Lipids, and Metabolism

Vorinostat suppresses hypoxia signaling by modulating nuclear translocation of hypoxia inducible factor 1 alpha

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Zhang, Chao, Yang, Chunzhang, Feldman, Michael J., Wang, Herui, Pang, Ying, Maggio, Dominic M., Zhu, Dongwang, Nesvick, Cody L. +6 more·2017·Oncotarget
DOI 10.18632/oncotarget.18125PMC PMC5593548
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Abstract

// Chao Zhang 1,2,* , Chunzhang Yang 3,* , Michael J. Feldman 4 , Herui Wang 4 , Ying Pang 2 , Dominic M. Maggio 4 , Dongwang Zhu 4 , Cody L. Nesvick 4 , Pauline Dmitriev 4 , Petra Bullova 2,5 , Prashant Chittiboina 4 , Roscoe O. Brady 4 , Karel Pacak 2 and Zhengping Zhuang 4 1 Department of Orthopedics, Xinqiao Hospital, The Third Military Medical University, Chongqing, China 2 Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA 3 Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA 4 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA 5 Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia * These authors have contributed equally to this work Correspondence to: Karel Pacak, email: // Zhengping Zhuang, email: // Keywords : HDACi, Hsp90, SAHA, HIF, hypoxia Received : December 14, 2016 Accepted : April 10, 2017 Published : May 23, 2017 Abstract Histone deacetylase inhibitors (HDACis) are a potent class of tumor-suppressive agents traditionally believed to exert their effects through loosening tightly-wound chromatin resulting in de-inhibition of various tumor suppressive genes. Recent literature however has shown altered intratumoral hypoxia signaling with HDACi administration not attributable to changes in chromatin structure. We sought to determine the precise mechanism of HDACi-mediated hypoxia signaling attenuation using vorinostat (SAHA), an FDA-approved class I/IIb/IV HDACi. Through an in-vitro and in-vivo approach utilizing cell lines for hepatocellular carcinoma (HCC), osteosarcoma (OS), and glioblastoma (GBM), we demonstrate that SAHA potently inhibits HIF-a nuclear translocation via direct acetylation of its associated chaperone, heat shock protein 90 (Hsp90). In the presence of SAHA we found elevated levels of acetyl-Hsp90, decreased interaction between acetyl-Hsp90 and HIF-a, decreased nuclear/cytoplasmic HIF-α expression, absent HIF-α association with its nuclear karyopharyin Importin, and markedly decreased HIF-a transcriptional activity. These changes were associated with downregulation of downstream hypoxia molecules such as endothelin 1, erythropoietin, glucose transporter 1, and vascular endothelial growth factor. Findings were replicated in an in-vivo Hep3B HRE-Luc expressing xenograft, and were associated with significant decreases in xenograft tumor size. Altogether, this study highlights a novel mechanism of action of an important class of chemotherapeutic.

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  • Vorinostat inhibits HIF-1α translation, impairs nuclear accumulation, and promotes ubiquitination-dependent proteasomal degradation, collectively suppressing HIF-1 transcriptional activity under hypoxia.

    “Mechanistically, vorinostat acts at multiple regulatory levels: it inhibits HIF-1α translation, impairs nuclear accumulation, and promotes ubiquitination-dependent proteasomal degradation, collectively suppressing HIF-1 transcriptional activity under hypoxia [351,352].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [352]

    The Abstract and Results report that vorinostat (SAHA) reduces HIF-α nuclear accumulation and transcriptional activity under hypoxia. The Results section on HIF-1/2α ubiquitination and degradation finds increased ubiquitin association and proteasome involvement, though it describes the ubiquitin-dependent mechanism as at least partial. The paper does not establish that vorinostat inhibits HIF-1α translation; its Discussion instead describes the observed reduction in HIF protein as post-translational. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Vorinostat exerts broad suppressive effects on HIF signaling, resulting in robust reductions in HIF-1α protein abundance.

    “Vorinostat (suberoylanilide hydroxamic acid), a pan-histone deacetylase (HDAC) inhibitor, exerts broad suppressive effects on HIF signaling, resulting in robust reductions in HIF-1α protein abundance [351,352].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [352]

    The Results section, “Effects of SAHA on HIF-1 response to hypoxia” (page unavailable), reports reduced HIF-1α protein and transcriptional activity in tumor cell lines. But “SAHA interferes with HIF-1/2α nuclear localization” (page unavailable) reports no change in total cellular HIF-1α at one low concentration and only a moderate decrease at a higher concentration; the larger reduction was in nuclear HIF-1α. Thus the paper supports broad suppression of HIF signaling, but not an unqualified claim of robust reductions in total HIF-1α protein abundance. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Vorinostat reduces HIF-2α protein levels, indicating a general role for HDAC activity in maintaining HIF-α stability and function.

    “Vorinostat similarly reduces HIF-2α protein levels, indicating a general role for HDAC activity in maintaining HIF-α stability and function [352].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [352]

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References 84 · Cited by 80

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Authors
Zhang, C., Yang, C., Feldman, M. J., Wang, H., Pang, Y., Maggio, D. M., Zhu, D., Nesvick, C. L., Dmitriev, P., Bullova, P., Chittiboina, P., Brady, R. O., Pacak, K., & Zhuang, Z.
Affiliations
  • Army Medical University (CN)
  • National Cancer Institute (US)
  • National Institutes of Health (US)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
  • Slovak Academy of Sciences (SK)
  • Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA
Corresponding author
  • Zhang, Chao
  • Yang, Chunzhang
ORCID
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2017-05-23
Volume
8
Issue
34
Pages
56110-56125
ISSN
1949-2553 (ISSN-L)
DOI
10.18632/oncotarget.18125
PMC
PMC5593548
OpenAlex
W2617150295
Cited by
80
References
84
Citations by year
2026: 4 · 2025: 8 · 2024: 7 · 2023: 13 · 2022: 7 · 2021: 13 · 2020: 13 · 2019: 10 · 2018: 5
FWCI
2.57
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Oncotarget (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Foundation for the National Institutes of Health
  • Howard Hughes Medical Institute
  • Doris Duke Charitable Foundation
  • Pfizer
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
vorinostat, histone deacetylase inhibitors, hypoxia signaling, hypoxia-inducible factor-1α, HIF-1α nuclear translocation, HSP90, HSP90 acetylation, intratumoral hypoxia, hepatocellular carcinoma, osteosarcoma, glioblastoma, tumor hypoxia, HIF-1α degradation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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